NF-κB is a protein that regulates the gene expression and is one of the so-called transcription factors. When normal cells are stimulated by an inflammatory cytokine such as interleukin-1 (IL-1) and TNF-α or by lipopolysaccharide, or ultraviolet rays, NF-κB is activated and migrates from the cytosol into the nucleus to bind to its specific nucleotide sequences on the genome DNA and thereby participate in the expression of various genes (see, T. S. Blackwell and J. W. Christman, Am. J. Respir. Cell. Mol. Biol., 17, 3-9 (1997)).
Among the genes of which the expression is under the control of NF-κB, many genes participate in an immunoinflammatory reaction, such as inflammatory cytokines (e.g., IL-1, IL-6, IL-8, TNF-α), cell adhesion molecules (e.g., ICAM-1, VCAM-1, ELAM-1) and inducible NO-synthase (iNOS) (see, T. Collins, M. A. Read, A. S. Neish, M. Z. Whitley, D. Thanos and T. Maniatis, Faseb. J., 899-909 (1995)). Furthermore, the inflammatory cytokine bound to its receptor is known to transduce a signal for activating NF-κB through various pathways and this is considered to make the inflammation worse. As such, in an inflammation, the activation of NF-κB is understood to be a cause or an exacerbation factor of a disease (see, P. A. Baeuerle and V. R. Baichwal, Adv. Immunol., 65, 111-137 (1997)).
In recent years, it has also been reported that HIV, HTLV-1, CMV and adenovirus activate NF-κB in host cells (see, B. J. Dezube, A. B. Pardee, L. A. Beckett, C. M. Ahlers, L. Ecto, J. Allen-Ryan, Z. A. Anisowicz, R. Sager and C. S. Crumpacker, J. Acquir. Immune Defic. Syndr., 5, 1099-1104 (1992); G. Nabel and D. Baltimore, Nature 326, 711-713 (1987); F. Fazely, B. J. Dezube, J. Allen-Ryan, A. B. Pardee and R. M. Ruprecht, Blood, 77, 1653-1656 (1991); and E. Munoz and A. Israel, Immunobiology, 193, 128-136 (1995)) and this activation of NF-κB is considered to participate in the self replication or increase of virus in the infected host cell.
Accordingly, the expression and induction of the inflammatory cytokines, the cell adhesion molecules gene and the viruses can be prevented altogether by inhibiting the activation of NF-κB and the NF-κB activation inhibitor is thought to be promising as a therapeutic agent for diseases directly or indirectly caused by the activation of NF-κB, particularly various inflammatory diseases and autoimmune diseases, or as a immunosuppressant or as a therapeutic agent for viral diseases.
At present, many antiinflammatory drugs are clinically used for the purpose of treating osteoarthritis, lumbago, rheumatoid arthritis and the like, however, there has been not found an effective for inhibiting the production of various inflammatory cytokines or the expression of cell adhesion molecules. NSAIDs (non-steroidal anti-inflammatory drugs), which are very often used, inhibit cyclooxygenase in the metabolic pathway of arachidonic acid cascade and thereby inhibit the production of prostaglandins, however, in general, they do not directly inhibit the production of cytokines. Steroids inhibit the production of a plurality of cytokines but these are known to bring about grave side effects such as undesired hormone activity, aggravation of infectious diseases, onset of peptic ulcers, and central effect and therefore are not amenable to a long-term administration.
It has also been reported in recent years that antiinframmatory drugs at high doses suppress the activation of NF-κB. (see, N. Auphan, J. A. DiDonato, C. Rosette, A. Helmberg and M. Karin, Science, 270, 286-290 (1995); R. E. Shackelford, P. B. Alford, Y. Xue, S. F. Thai, D. O. Adams and S. Pizzo, Mol. Phamacol., 52, 421-429 (1997); and V. Bitko, A. Velazquez, L. Yang, Y. C. Yang and S. Barik, Virology, 232, 369-378 (1997)). For example, benzoic acid derivatives such as salicylic acid and aspirin have been reported to inhibit the activation of NF-κB (see, Science, 265, 956-959 (1994)), however, insufficient efficacy and side effects due to various pharmacological actions have been pointed out as problems.
Accordingly, development of medicines capable of more specifically inhibiting the activation of NF-κB and having higher safety is required and many researchers are making investigations for NF-κB activation inhibitors.
As the NF-κB activation inhibitors, there have been recently proposed, for example, isocarbazole derivatives (see, Japanese Unexamined Patent Publication (Kokai) Nos. 8-319238 and 2000-169479), isoquinoline derivatives (see, Kokai Nos. 10-87491 and 11-180873), benzoquinone derivatives (see, Kokai Nos. 7-291859 and 11-266872), β-lactam derivatives (see, Kokai No. 11-71278), lignan derivatives (see, Kokai No. 10-175861), benzylidene derivatives (see, PCT/JP98/04774), pyrimidine-5-carboxamide derivatives (see, WO97/09315 and WO97/09325), cyclopentabenzofuran derivatives (see, WO00/08007), benzene derivatives (see, WO00/15603), pyrrolidine dithiocarbonate (PDTC) (see, Eur. J. Immunol., 29, 1890-1900 (1999)), 3-deazaadenosine (DZA) (see, J. Biol. Chem., 274, 27, 18981-18988 (1999)) and 2,2′-bi-1H-pyrrole derivatives (see, J. Immunol., 162, 7102-7109 (1999)).
In many cases, the mechanisms of action inhibiting the activation are not clearly known, however, as for the substances considered to inhibit the activation by antioxidant effects or activities of inhibiting protein phosphorylation, the stability or the specificity seems to be a problem. Furthermore, at present, drugs having a enough potency to inhibit transcription factor NF-κB activation are not found.
On the other hand, Kokai No. 7-291859 discloses the following benzoquinone derivative (A) as an NF-κB activation inhibitor: 
Also, Kokai No. 11-266872 discloses a novel method for screening substances capable of inhibiting the activation of NF-κB and a substance capable of inhibiting the activation of NF-κB found by the method, the following benzoquinone derivative (B) was described: 
However, these compounds are not sufficiently high in efficacy as NF-κB activation inhibitors. A substance having a stronger NF-κB inhibitory activity is required.